Induction of GADD45α protects M17 neuroblastoma cells against MPP*.

Growth arrest and DNA-damage-inducible protein 45α (GADD45α) is an important member of the family of growth arrest and DNA damage-inducible (GADD) proteins. The expression patterns and possible roles of GADD45α in Parkinson's disease (PD) are so far less understood. In this study, we found that 1-methyl-4-phenylpyridinium (MPP+) treatment up-regulates the expression of GADD45α in both a time-dependent manner and a dose-dependent manner in human dopamine neuroblastoma M17 cells. The up-regulation of GADD45α was abolished by pretreatment with the c-Jun N-terminal kinases (JNK) inhibitor SP600125 but not the p38 specific inhibitor SB203580. Further study revealed that c-Jun silencing abolished the effects of MPP+ on the expression of GADD45α. Important, ChIP studies verified the ability of c-Jun to bind to the GADD45 promoter. In addition, we found that inhibition of GADD45α by small RNA interference exacerbates the impaired cell viability, LDH release, and apoptosis induced by MPP+. Correspondingly, silence of GADD45 exacerbated Caspase-3 activation induced by MPP+. These data suggested a neuroprotective effect of GADD45α against MPP+ neurotoxicity.